Fused aminopiperidines as dipeptidyl peptidase-4 inhibitors for the treatment or prevention of diabetes

ABSTRACT

The present invention is directed to novel substituted fused aminopiperidines of structural formula (I) which are inhibitors of the dipeptidyl peptidase-4 enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-4 enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-4 enzyme is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US2006/047068, filed 8 Dec. 2006, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/750,135, filed 14Dec. 2005.

FIELD OF THE INVENTION

The present invention relates to novel substituted fusedaminopiperidines which are inhibitors of the dipeptidyl peptidase-4enzyme (“DPP-4 inhibitors”) and which are useful in the treatment orprevention of diseases in which the dipeptidyl peptidase-4 enzyme isinvolved, such as diabetes and particularly Type 2 diabetes. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which the dipeptidylpeptidase-4 enzyme is involved.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of Type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of Type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensitization that is observed withthe glitazones. Newer PPAR agonists that are being tested for treatmentof Type II diabetes are agonists of the alpha, gamma or delta subtype,or a combination of these, and in many cases are chemically differentfrom the glitazones (i.e., they are not thiazolidinediones). Seriousside effects (e.g. liver toxicity) have occurred with some of theglitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-4 (“DPP-4”)enzyme are also under investigation as drugs that may be useful in thetreatment of diabetes, and particularly Type 2 diabetes. See for exampleWO 97/40832, WO 98/19998, U.S. Pat. No. 5,939,560, Bioorg. Med. Chem.Lett., 6: 1163-1166 (1996); and Bioorg. Med. Chem. Lett., 6: 2745-2748(1996). The usefulness of DPP-4 inhibitors in the treatment of Type 2diabetes is based on the fact that DPP-4 in vivo readily inactivatesglucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).GLP-1 and GIP are incretins and are produced when food is consumed. Theincretins stimulate production of insulin. Inhibition of DPP-4 leads todecreased inactivation of the incretins, and this in turn results inincreased effectiveness of the incretins in stimulating production ofinsulin by the pancreas. DPP-4 inhibition therefore results in anincreased level of serum insulin. Advantageously, since the incretinsare produced by the body only when food is consumed, DPP-4 inhibition isnot expected to increase the level of insulin at inappropriate times,such as between meals, which can lead to excessively low blood sugar(hypoglycemia). Inhibition of DPP-4 is therefore expected to increaseinsulin without increasing the risk of hypoglycemia, which is adangerous side effect associated with the use of insulin secretagogues.

DPP-4 inhibitors also have other therapeutic utilities, as discussedherein. DPP-4 inhibitors have not been studied extensively to date,especially for utilities other than diabetes. New compounds are neededso that improved DPP-4 inhibitors can be found for the treatment ofdiabetes and potentially other diseases and conditions. The therapeuticpotential of DPP-4 inhibitors for the treatment of Type 2 diabetes isdiscussed by D. J. Drucker in Exp. Opin. Invest. Drugs, 12: 87-100(2003) and by K. Augustyns, et al., in Exp. Opin. Ther. Patents, 13:499-510 (2003).

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted fusedaminopiperidines which are inhibitors of the dipeptidyl peptidase-4enzyme (“DPP-4 inhibitors”) and which are useful in the treatment orprevention of diseases in which the dipeptidyl peptidase-4 enzyme isinvolved, such as diabetes and particularly Type 2 diabetes. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which the dipeptidylpeptidase-4 enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted fused aminopiperidines thatare useful as inhibitors of dipeptidyl peptidase-4. Compounds of thepresent invention are described by structural formula I:

and pharmaceutically acceptable salts thereof; wherein

-   -   each n is independently 0, 1, 2 or 3;    -   Ar is phenyl unsubstituted or substituted with one to five R²        substituents;    -   each R² is independently selected from the group consisting of        -   halogen,        -   cyano,        -   hydroxy,        -   C₁₋₆ alkyl, unsubstituted or substituted with one to five            halogens, and        -   C₁₋₆ alkoxy, unsubstituted or substituted with one to five            halogens;    -   W, X, Y and Z are each independently N or CR¹, with the provisos        that (a) when X is N, then one of W, Y or Z must be N and (b)        when Y is N, then one of W, X or Z must be N;    -   each R¹ is independently selected from the group consisting of        -   hydrogen,        -   hydroxy,        -   halogen,        -   cyano,        -   nitro,        -   C₁₋₁₀ alkoxy, wherein alkoxy is unsubstituted or substituted            with one to five substituents independently selected from            halogen or hydroxy,        -   C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted            with one to five substituents independently selected from            halogen or hydroxy,        -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted            with one to five substituents independently selected            hydroxy, halogen, cyano, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆            alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are            unsubstituted or substituted with one to five halogens,        -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or            substituted with one to three substituents independently            selected from hydroxy, halogen, cyano, CO₂H, C₁₋₆            alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl            and alkoxy are unsubstituted or substituted with one to five            halogens,        -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is            unsubstituted or substituted with one to three substituents            independently selected from oxo, hydroxy, halogen, cyano,            CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,            wherein alkyl and alkoxy are unsubstituted or substituted            with one to five halogens,        -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is            unsubstituted or substituted with one to three substituents            independently selected from halogen, hydroxy, cyano, CO₂H,            C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein            alkyl and alkoxy are unsubstituted or substituted with one            to five halogens,        -   (CH₂)_(n)—COOH,        -   (CH₂)_(n)—COOC₁₋₆ alkyl,        -   (CH₂)_(n)—NR³R⁴,        -   (CH₂)_(n)—CONR³R⁴,        -   (CH₂)_(n)—OCONR³R⁴,        -   (CH₂)_(n)—SO₂NR³R⁴,        -   (CH₂)_(n)—SO₂R⁵,        -   (CH₂)_(n)—SOR⁵,        -   (CH₂)_(n)—SR⁶,        -   (CH₂)_(n)—NR⁶SO₂R⁵,        -   (CH₂)_(n)—NR⁶CONR³R⁴,        -   (CH₂)_(n)—NR⁶COR⁶, and        -   (CH₂)_(n)—NR⁶CO₂R⁵;            wherein any individual methylene (CH₂) carbon atom in            (CH₂)_(n) is unsubstituted or substituted with one to two            groups independently selected from halogen, hydroxy, C₁₋₄            alkyl, and C₁₋₄ alkoxy, wherein alkyl and alkoxy are            unsubstituted or substituted with one to five halogens;    -   R³ and R⁴ are each independently selected from the group        consisting of        -   hydrogen,        -   (CH₂)_(n)-phenyl,        -   (CH₂)_(n)—C₃₋₆ cycloalkyl, and        -   C₁₋₆ alkyl,            wherein alkyl is unsubstituted or substituted with one to            five substituents independently selected from halogen and            hydroxy and wherein phenyl and cycloalkyl are unsubstituted            or substituted with one to five substituents independently            selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,            wherein alkyl and alkoxy are unsubstituted or substituted            with one to five halogens;    -   or R³ and R⁴ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidine,        pyrrolidine, piperidine, piperazine, and morpholine wherein said        heterocyclic ring is unsubstituted or substituted with one to        three substituents independently selected from halogen, hydroxy,        C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are        unsubstituted or substituted with one to five halogens;    -   each R⁵ is independently C₁₋₆ alkyl, wherein alkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen and hydroxy; and    -   R⁶ is hydrogen or R⁵.

In one embodiment of the compounds of the present invention, each R² isindependently selected from the group consisting of fluorine, chlorine,methyl, and trifluoromethyl.

In a second embodiment of the compounds of the present invention, W isN; and X, Y, and Z are CR¹.

In a third embodiment of the compounds of the present invention, Z is N;and W, X, and Y are CR¹.

In a fourth embodiment of the compounds of the present invention, W andY are N; and X and Z are CR¹.

In a fifth embodiment of the compounds of the present invention, X and Zare N; and W and Y are CR¹.

In a sixth embodiment of the compounds of the present invention, W and Xare N; and Y and Z are CR¹.

In a seventh embodiment of the compounds of the present invention, X andY are N; and W and Z are CR¹.

In an eighth embodiment of the compounds of the present invention, Y andZ are N; and W and X are CR¹.

In a ninth embodiment of the compounds of the present invention, W and Zare N; and X and Y are CR¹.

In a tenth embodiment of the compounds of the present invention, thereare provided compounds of structural formulae Ia and Ib of the indicatedstereochemical configuration having a trans orientation of the Ar andNH₂ substituents on the two stereogenic carbon atoms marked with an *:

wherein Ar, W, X, Y, and Z are as described above.

In a class of this tenth embodiment, there are provided compounds ofstructural formula Ia of the indicated absolute stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituentson the two stereogenic carbon atoms marked with an *:

wherein Ar, W, X, Y, and Z are as described above.

Nonlimiting examples of compounds of the present invention that areuseful as dipeptidyl peptidase-4 inhibitors are the following structureshaving the indicated absolute stereochemical configurations at the twostereogenic fused piperidine carbon atoms:

and pharmaceutically acceptable salts thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃₋₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁₋₆ is intended.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₁₀ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₁₀ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

The term “heterocyclyl” refers to saturated or unsaturated non-aromaticrings or ring systems containing at least one heteroatom selected fromO, S and N, further including the oxidized forms of sulfur, namely SOand SO₂. Examples of heterocycles include tetrahydrofuran (THF),dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one, pyridone, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls also include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, 2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl),oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, imidazo[1,2-a]pyridinyl,[1,2,4-triazolo][4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4-triazolo][1,5-a]pyridinyl, 2-oxo-1,3-benzoxazolyl,4-oxo-3H-quinazolinyl, 3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,and the like. For heterocyclyl and heteroaryl groups, rings and ringsystems containing from 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The compounds of the present invention contain one or more asymmetriccenters and can thus occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures, and individual diastereomers. Inparticular the compounds of the present invention have an asymmetriccenter at the stereogenic carbon atoms marked with an * in formulae Iaand Ib. Additional asymmetric centers may be present depending upon thenature of the various substituents on the molecule. Each such asymmetriccenter will independently produce two optical isomers and it is intendedthat all of the possible optical isomers and diastereomers in mixturesand as pure or partially purified compounds are included within theambit of this invention. The present invention is meant to comprehendall such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formulae Ia and Ib show the preferredstereochemistry at the stereogenic carbon atoms to which are attachedthe NH₂ and Ar groups on the cyclohexane ring.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethyl amine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-4 enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-4enzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-4 enzymeactivity in humans and animals comprising combining a compound of thepresent invention with a pharmaceutically acceptable carrier or diluent.

More particularly, the present invention is directed to the use of acompound of structural formula I in the manufacture of a medicament foruse in treating a condition selected from the group consisting ofhyperglycemia, Type 2 diabetes, obesity, and a lipid disorder in amammal, wherein the lipid disorder is selected from the group consistingof dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-4 enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-4 enzyme activity may be demonstratedby methodology known in the art. Inhibition constants are determined asfollows. A continuous fluorometric assay is employed with the substrateGly-Pro-AMC, which is cleaved by DPP-4 to release the fluorescent AMCleaving group. The kinetic parameters that describe this reaction are asfollows: K_(m)=50 μM; k_(cat)=75 s⁻¹; k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. Atypical reaction contains approximately 50 μM enzyme, 50 μM Gly-Pro-AMC,and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a total reactionvolume of 100 μl. Liberation of AMC is monitored continuously in a96-well plate fluorometer using an excitation wavelength of 360 nm andan emission wavelength of 460 nm. Under these conditions, approximately0.8 μM AMC is produced in 30 minutes at 25 degrees C. The enzyme used inthese studies was soluble (transmembrane domain and cytoplasmicextension excluded) human protein produced in a baculovirus expressionsystem (Bac-To-Bac, Gibco BRL). The kinetic constants for hydrolysis ofGly-Pro-AMC and GLP-1 were found to be in accord with literature valuesfor the native enzyme. To measure the dissociation constants forcompounds, solutions of inhibitor in DMSO were added to reactionscontaining enzyme and substrate (final DMSO concentration is 1%). Allexperiments were conducted at room temperature using the standardreaction conditions described above. To determine the dissociationconstants (K_(i)), reaction rates were fit by non-linear regression tothe Michaelis-Menton equation for competitive inhibition. The errors inreproducing the dissociation constants are typically less than two-fold.

In particular, the compounds of the following examples had activity ininhibiting the dipeptidyl peptidase-4 enzyme in the aforementionedassays, generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors the dipeptidyl peptidase-4 enzyme activity.

Dipeptidyl peptidase-4 enzyme (DPP-4) is a cell surface protein that hasbeen implicated in a wide range of biological functions. It has a broadtissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DPP-4 is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

Type II Diabetes and Related Disorders: It is well established that theincretins GLP-1 and GIP are rapidly inactivated in vivo by DPP-4.Studies with DPP-4^((-/-))-deficient mice and preliminary clinicaltrials indicate that DPP-4 inhibition increases the steady stateconcentrations of GLP-1 and GIP, resulting in improved glucosetolerance. By analogy to GLP-1 and GIP, it is likely that other glucagonfamily peptides involved in glucose regulation are also inactivated byDPP-4 (eg. PACAP). Inactivation of these peptides by DPP-4 may also playa role in glucose homeostasis. The DPP-4 inhibitors of the presentinvention therefore have utility in the treatment of type II diabetesand in the treatment and prevention of the numerous conditions thatoften accompany Type II diabetes, including Syndrome X (also known asMetabolic Syndrome), reactive hypoglycemia, and diabetic dyslipidemia.Obesity, discussed below, is another condition that is often found withType II diabetes that may respond to treatment with the compounds ofthis invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidemia, hypertension, and increased cardiovascular risk.Therefore, DPP-4 inhibitors may also be useful to treat hypertensionassociated with this condition.

Obesity: DPP-4 inhibitors may be useful for the treatment of obesity.This is based on the observed inhibitory effects on food intake andgastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1in humans significantly decreases food intake and slows gastric emptying(Am. J. Physiol., 277: R910-R916 (1999)). ICV administration of GLP-1 inrats and mice also has profound effects on food intake (Nature Medicine,2: 1254-1258 (1996)). This inhibition of feeding is not observed inGLP-1R^((-/-)) mice, indicating that these effects are mediated throughbrain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 isalso regulated by DPP-4. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine,6: 802-807 (2000)). In addition, studies with DPP-4 deficient micesuggest that these animals are resistant to diet-induced obesity andassociated pathology (e.g. hyperinsulinonemia).Cardiovascular Disease: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction, leadingto improved left ventricular function and reduced mortality afterprimary angioplasty (Circulation, 109: 962-965 (2004)). GLP-1administration is also useful for the treatment of left ventricularsystolic dysfunction in dogs with dilated cardiomyopathy and ischemicinduced left ventricular dysfunction, and thus may prove useful for thetreatment of patients with heart failure (US2004/0097411). DPP-4inhibitors are expected to show similar effects through their ability tostabilize endogenous GLP-1.Growth Hormone Deficiency: DPP-4 inhibition may be useful for thetreatment of growth hormone deficiency, based on the hypothesis thatgrowth-hormone releasing factor (GRF), a peptide that stimulates releaseof growth hormone from the anterior pituitary, is cleaved by the DPP-4enzyme in vivo (WO 00/56297). The following data provide evidence thatGRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitroto generate the inactive product GRF[3-44] (BBA 122: 147-153 (1992));(2) GRF is rapidly degraded in plasma to GRF[344]; this is prevented bythe DPP-4 inhibitor diprotin A; and (3) GRF[3-44] is found in the plasmaof a human GRF transgenic pig (J. Clin. Invest., 83: 1533-1540 (1989)).Thus DPP-4 inhibitors may be useful for the same spectrum of indicationswhich have been considered for growth hormone secretagogues.Intestinal Injury: The potential for using DPP-4 inhibitors for thetreatment of intestinal injury is suggested by the results of studiesindicating that glucagon-like peptide-2 (GLP-2), a likely endogenoussubstrate for DPP-4, may exhibit trophic effects on the intestinalepithelium (Regulatory Peptides, 90: 27-32 (2000)). Administration ofGLP-2 results in increased small bowel mass in rodents and attenuatesintestinal injury in rodent models of colitis and enteritis.Immunosuppression: DPP-4 inhibition may be useful for modulation of theimmune response, based upon studies implicating the DPP-4 enzyme in Tcell activation and in chemokine processing, and efficacy of DPP-4inhibitors in in vivo models of disease. DPP-4 has been shown to beidentical to CD26, a cell surface marker for activated immune cells. Theexpression of CD26 is regulated by the differentiation and activationstatus of immune cells. It is generally accepted that CD26 functions asa co-stimulatory molecule in in vitro models of T cell activation. Anumber of chemokines contain proline in the penultimate position,presumably to protect them from degradation by non-specificaminopeptidases. Many of these have been shown to be processed in vitroby DPP-4. In several cases (RANTES, LD78-beta, MDC, eotaxin,SDF-1alpha), cleavage results in an altered activity in chemotaxis andsignaling assays. Receptor selectivity also appears to be modified insome cases (RANTES). Multiple N-terminally truncated forms of a numberof chemokines have been identified in in vitro cell culture systems,including the predicted products of DPP-4 hydrolysis.

DPP-4 inhibitors have been shown to be efficacious immunosuppressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DPP-4, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation 63: 1495-1500 (1997)). DPP-4 inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology. 19:15-24 (1997) andImmunopharmacology, 40: 21-26 (1998)]. DPP-4 is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday, 20: 367-375 (1999)).

HIV Infection: DPP-4 inhibition may be useful for the treatment orprevention of HIV infection or AIDS because a number of chemokines whichinhibit HIV cell entry are potential substrates for DPP-4 (ImmunologyToday 20: 367-375 (1999)). In the case of SDF-1alpha, cleavage decreasesantiviral activity (PNAS, 95: 6331-6 (1998)). Thus, stabilization ofSDF-1alpha through inhibition of DPP-4 would be expected to decrease HIVinfectivity.Hematopoiesis: DPP-4 inhibition may be useful for the treatment orprevention of hematopoiesis because DPP-4 may be involved inhematopoiesis. A DPP-4 inhibitor, Val-Boro-Pro, stimulated hematopoiesisin a mouse model of cyclophosphamide-induced neutropenia (WO 99/56753).Neuronal Disorders: DPP-4 inhibition may be useful for the treatment orprevention of various neuronal or psychiatric disorders because a numberof peptides implicated in a variety of neuronal processes are cleaved invitro by DPP-4. A DPP-4 inhibitor thus may have a therapeutic benefit inthe treatment of neuronal disorders. Endomorphin-2, beta-casomorphin,and substance P have all been shown to be in vitro substrates for DPP-4.In all cases, in vitro cleavage is highly efficient, with k_(cat)/K_(m)about 10⁶ M⁻¹s⁻¹ or greater. In an electric shock jump test model ofanalgesia in rats, a DPP-4 inhibitor showed a significant effect thatwas independent of the presence of exogenous endomorphin-2 (BrainResearch, 815: 278-286 (1999)). Neuroprotective and neuroregenerativeeffects of DPP-4 inhibitors were also evidenced by the inhibitors'ability to protect motor neurons from excitotoxic cell death, to protectstriatal innervation of dopaminergic neurons when administeredconcurrently with MPTP, and to promote recovery of striatal innervationdensity when given in a therapeutic manner following MPTP treatment [seeYong-Q. Wu, et al., “Neuroprotective Effects of Inhibitors of DipeptidylPeptidase-4 In Vitro and In Vivo,” Int. Conf. On DipeptidvlAminopeptidases: Basic Science and Clinical Applications, Sep. 26-29,2002 (Berlin, Germany)].Anxiety: Rats naturally deficient in DPP-4 have an anxiolytic phenotype(WO 02/34243; Karl et al., Physiol. Behav. 2003). DPP-4 deficient micealso have an anxiolytic phenotype using the porsolt and light/darkmodels. Thus DPP-4 inhibitors may prove useful for treating anxiety andrelated disorders.Memory and Cognition: GLP-1 agonists are active in models of learning(passive avoidance, Morris water maze) and neuronal injury(kainate-induced neuronal apoptosis) as demonstrated by During et al.(Nature Med. 9: 1173-1179 (2003)). The results suggest a physiologicalrole for GLP-1 in learning and neuroprotection. Stabilization of GLP-1by DPP-4 inhibitors are expected to show similar effectsMyocardial Infarction: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction(Circulation, 109: 962-965 (2004)). DPP-4 inhibitors are expected toshow similar effects through their ability to stabilize endogenousGLP-1.Tumor Invasion and Metastasis: DPP-4 inhibition may be useful for thetreatment or prevention of tumor invasion and metastasis because anincrease or decrease in expression of several ectopeptidases includingDPP-4 has been observed during the transformation of normal cells to amalignant phenotype (J. Exp. Med., 190: 301-305 (1999)). Up- ordown-regulation of these proteins appears to be tissue and cell-typespecific. For example, increased CD26/DPP-4 expression has been observedon T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derivedthyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus,DPP-4 inhibitors may have utility in the treatment of such carcinomas.Benign Prostatic Hypertrophy: DPP-4 inhibition may be useful for thetreatment of benign prostatic hypertrophy because increased DPP-4activity was noted in prostate tissue from patients with BPH (Eur. J.Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).Sperm mobility/male contraception: DPP-4 inhibition may be useful forthe altering sperm motility and for male contraception because inseminal fluid, prostatosomes, prostate derived organelles important forsperm motility, possess very high levels of DPP-4 activity (Eur. J.Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).Gingivitis: DPP-4 inhibition may be useful for the treatment ofgingivitis because DPP-4 activity was found in gingival crevicular fluidand in some studies correlated with periodontal disease severity (Arch.Oral Biol., 37: 167-173 (1992)).Osteoporosis: DPP-4 inhibition may be useful for the treatment orprevention of osteoporosis because GIP receptors are present inosteoblasts.Stem Cell Transplantation: Inhibition of DPP-4 on donor stem cells hasbeen shown to lead to an enhancement of their bone marrow homingefficiency and engraftment, and an increase in survival in mice(Christopherson, et al., Science, 305:1000-1003 (2004)). Thus DPP-4inhibitors may be useful in bone marrow transplantation.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type 2 diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, (35) anxiety,(36) memory deficit, (37) cognition deficit, (38) stroke, (39)Alzheimer's disease, and other conditions that may be treated orprevented by inhibition of DPP-4.

The subject compounds are further useful in a method for the preventionor treatment of the aforementioned diseases, disorders and conditions incombination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DPP-4) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, and the like) and other PPAR ligands,including PPARα/γ dual agonists, such as KRP-297, muraglitazar,naveglitazar, tesaglitazar, TAK-559, PPARα agonists, such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),and selective PPARγ modulators (SPPARγM's), such as disclosed in WO02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408,and WO 2004/066963; (ii) biguanides such as metformin and phenformin,and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such as nateglinideand repaglinide;

(e) α-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists, such as those disclosed in WO97/16442; WO 98/04528, WO 98/21957; WO 98/22108; WO 98/22109; WO99/01423, WO 00/39088, and WO 00/69810; WO 2004/050039; and WO2004/069158;

(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists,such as exendin-4 (exenatide), liraglutide (N,N-2211), CJC-1131,LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, andGIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as naveglitazar and muraglitazar, (vi)inhibitors of cholesterol absorption, such as beta-sitosterol andezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, suchas avasimibe, and (viii) antioxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,CB1 receptor inverse agonists and antagonists, β₃ adrenergic receptoragonists, melanocortin-receptor agonists, in particular melanocortin-4receptor agonists, ghrelin antagonists, bombesin receptor agonists (suchas bombesin receptor subtype-3 agonists), cholecystokinin 1 (CCK-1)receptor agonists, and melanin-concentrating hormone (MCH) receptorantagonists;

(m) ileal bile acid transporter inhibitors;

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids,azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) antihypertensive agents, such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losartan, candesartan, irbesartan, valsartan, telmisartan, andeprosartan), beta blockers and calcium channel blockers;

(p) glucokinase activators (GKAs), such as those disclosed in WO03/015774; WO 04/076420; and WO 04/081001;

(q) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such as thosedisclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO 04/058741;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib; and

(s) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476.

Dipeptidyl peptidase-4 inhibitors that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,699,871;WO 02/076450 (3 Oct. 2002); WO 03/004498 (16 Jan. 2003); WO 03/004496(16 Jan. 2003); EP 1 258 476 (20 Nov. 2002); WO 02/083128 (24 Oct.2002); WO 02/062764 (15 Aug. 2002); WO 03/000250 (3 Jan. 2003); WO03/002530 (9 Jan. 2003); WO 03/002531 (9 Jan. 2003); WO 03/002553 (9Jan. 2003); WO 03/002593 (9 Jan. 2003); WO 03/000180 (3 Jan. 2003); WO03/082817 (9 Oct. 2003); WO 03/000181 (3 Jan. 2003); WO 04/007468 (22Jan. 2004); WO 04/032836 (24 Apr. 2004); WO 04/037169 (6 May 2004); andWO 04/043940 (27 May 2004). Specific DPP-4 inhibitor compounds includeisoleucine thiazolidide (P32/98); NVP-DPP-728; vildagliptin (LAF 237);P93/01; and saxagliptin (BMS 477118).

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoidCB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, bombesin receptor agonists, and melanin-concentratinghormone (MCH) receptor antagonists. For a review of anti-obesitycompounds that can be combined with compounds of structural formula I,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); and J. A. Fernandez-Lopez, et al., “Pharmacological Approachesfor the Treatment of Obesity,” Drugs, 62: 915-944 (2002).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB1 receptor antagonists that can be combined with compoundsof formula I include those disclosed in PCT Publication WO 03/007887;U.S. Pat. No. 5,624,941, such as rimonabant; PCT Publication WO02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT Publication WO98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S.Pat. No. 5,532,237; U.S. Pat. No. 5,292,736; PCT Publication WO05/000809; PCT Publication WO 03/086288; PCT Publication WO 03/087037;PCT Publication WO 04/048317; PCT Publication WO 03/007887; PCTPublication WO 03/063781; PCT Publication WO 03/075660; PCT PublicationWO 03/077847; PCT Publication WO 03/082190; PCT Publication WO03/082191; PCT Publication WO 03/087037; PCT Publication WO 03/086288;PCT Publication WO 04/012671; PCT Publication WO 04/029204; PCTPublication WO 04/040040; PCT Publication WO 01/64632; PCT PublicationWO 01/64633; and PCT Publication WO 01/64634.

Melanocortin-4 receptor (MC4R) agonists useful in the present inventioninclude, but are not limited to, those disclosed in U.S. Pat. No.6,294,534, U.S. Pat. Nos. 6,350,760, 6,376,509, 6,410,548, 6,458,790,U.S. Pat. No. 6,472,398, U.S. Pat. No. 5,837,521, U.S. Pat. No.6,699,873, which are hereby incorporated by reference in their entirety;in US Patent Application Publication Nos. US 2002/0004512,US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060,US2003/0092732, US2003/109556, US 2002/0177151, US 2002/187932, US2003/0113263, which are hereby incorporated by reference in theirentirety; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO2004/078717, WO 2004/037797, WO 01/58891, WO 02/070511, WO 02/079146, WO03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO02/059107, WO 02/059108, WO 02/059117, WO 02/085925, WO 03/004480, WO03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO 04/048345, WO02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO03/040107, WO 03/040117, WO 03/040118, WO 03/013509, WO 03/057671, WO02/079753, WO 02//092566, WO 03/-093234, WO 03/095474, and WO 03/104761.

The potential utility of safe and effective activators of glucokinase(GKAs) for the treatment of diabetes is discussed in J. Grimsby et al.,“Allosteric Activators of Glucokinase: Potential Role in DiabetesTherapy,” Science, 301: 370-373 (2003).

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-4 enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared fromintermediates such as those of formula II and an ortho-haloaminoarene oran ortho-halonitroarene such as III using standard coupling conditionsfollowed by condensation and deprotection. The preparation of theseintermediates is described in the following Schemes, wherein Ar is asdefined above and P is a suitable nitrogen protecting group such astert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), and9-fluorenylmethoxycarbonyl (Fmoc).

Compounds of formula IIa may be prepared from intermediate 6 using aroute described in Scheme 1. Intermediates of formula 6 are known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One route described in W. H. Mooset al., J. Org. Chem., 46: 5064-5074 (1981) is illustrated in Scheme 1.A substituted benzaldehyde 1 is treated with trimethyl or triethylphosphonoacetate 2 in the presence of a base such as1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) to provide the aryl enoate 3.Conjugate addition of ethyl or methyl cyanoacetate 4 to enoate 3 in thepresence of sodium methoxide provides 5 as a mixture of stereoisomers ateach chiral center. Reduction of the nitrile of 5 using catalytichydrogenation with, for example, hydrogen gas and a platinum (IV) oxidecatalyst, is followed by treatment of the product amine with basicmethanol to induce cyclization and equilibration of the stereoisomers topredominantly the trans stereoisomer. This may be followed byre-esterification of the intermediate using, for example,trimethylsilyldiazomethane to give compound 6 as predominantly the transisomer. Protection of lactam 6 with 4,4′-dimethoxybenzhydrol followingliterature conditions (C. Henneuse, et. al. Synthesis, 495 (1996))provides the corresponding N-protected lactam. Subsequent hydrolysis ofthe methyl ester with, for example, lithium hydroxide then provides acid7 wherein P=(4-MeOPh)₂CH. Acid 7 may then be subjected to Curtiusrearrangement following literature conditions (D. A. Evans, et al. J.Org. Chem., 64: 6411-6417 (1999)) to give the corresponding benzylcarbamate, which is deprotected under hydrogenation conditions in thepresence of di-tert-butyl dicarbonate to provide intermediate 8.Deprotection of the lactam of 8 using an oxidant such as cerium ammoniumnitrate (CAN) in a solvent such as acetonitrile and water provides IIa.

Compounds of formula I may be prepared as illustrated in Scheme 2 fromintermediate IIa described above and intermediate IIIa, wherein U is Cl,Br, I, or triflate. Intermediates IIIa are either commercially availableor known in the literature. Intermediates 9 may be prepared by heatingIIa and IIIa together in the presence of a copper salt such as copper(I) iodide and N,N′-dimethylethylenediamine in the presence of a basesuch as potassium carbonate or potassium phosphate in solvents such astoluene or ethylene glycol dimethyl ether (DME) according to proceduresoutlined in A. Klapars, et. J. Am. Chem. Soc. 124: 7421-7428 (2002) andreferences contained therein. The nitro group of 9 is then reduced with,for example, Raney nickel and hydrogen gas in the presence of a solventsuch as tetrahydrofuran/water or ethanol to give the correspondingaminoarene 10. The aminoarene 10 is then cyclized to the fusedbenzimidazole 11 by heating in the presence of an acid such as aceticacid in a solvent such as toluene. The protecting group of 11 is thenremoved with, for example, trifluoroacetic acid or methanolic hydrogenchloride in the case of Boc to give the desired amine I. The product ispurified, if necessary, by crystallization, trituration, preparativethin layer chromatography, flash chromatography on silica gel, such aswith a Biotage® apparatus, or HPLC. Compounds that are purified byreverse phase HPLC may be isolated as the corresponding salt.Purification of intermediates is achieved in the same manner.

Alternatively, intermediates 11 may be prepared as illustrated in Scheme3 from intermediate IIa described above and aminoarene IIIb, wherein Uis Cl, Br, I, or triflate. Aminoarenes IIIb are either commerciallyavailable or known in the literature. Intermediates 11 may be preparedby heating II and IIIb together in the presence of a copper salt such ascopper (I) iodide and N,N′-dimethylethylenediamine in the presence of abase such as potassium carbonate or potassium phosphate in solvents suchas toluene or ethylene glycol dimethyl ether (DME) according to theprocedure outlined in A. Klapars, et. al. J. Am. Chem. Soc., 124:7421-7428 (2002) and references contained therein. Intermediate 11 maythen be deprotected and purified as described in Scheme 2 above.

In some cases the product I or synthetic intermediates illustrated inthe above schemes may be further modified, for example, by manipulationof substituents on Ar or R¹. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, arylation, acylation,and hydrolysis reactions that are commonly known to those skilled in theart.

One such example is illustrated in Scheme 4. Intermediate 12 may beprepared by reaction of IIa and 2,4-dichloro-6-methylpyridin-3-amineusing conditions described in Scheme 3. Further manipulation ofintermediate 12 may be accomplished by treatment with hydrogen in thepresence of a catalyst such as palladium on carbon to give compound 13.Deprotection of 13 may be accomplished, for example, by treatment withan acid such as hydrogen chloride or trifluoroacetic acid in a solventsuch as dichloromethane or dioxane to provide compound Ic.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

tert-Butyl[(3R,4R)-6-oxo-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamateStep A: Ethyl 3-(2,4,5-trifluorophenyl)acrylate

To a solution of 10 g (62 mmol) of 2,4,5-trifluorobenzaldehyde and 14 mL(70 mmol) of triethyl phosphonoacetate in 200 mL of tetrahydrofuran wasadded 11 mL (75 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene. Thesolution was stirred at ambient temperature for 4 h, then concentratedin vacuo and dissolved in 800 mL of a 10:1 solution of hexane/ethylacetate. The resulting solution was washed sequentially with 1Nhydrochloric acid, saturated aqueous sodium bicarbonate solution, andsaturated aqueous brine (200 mL each). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield acrude oil. The crude material was then purified by flash chromatographyon a Biotage Horizon® system (silica gel, 0 to 15% ethyl acetate/hexanesgradient) to give ethyl 3-(2,4,5-trifluorophenyl)acrylate as a colorlessoil. ¹H NMR (CDCl₃): δ 7.71 (d, J=16.2 Hz, 1H), 7.37 (ddd, J=17.1, 8.7,1.8 Hz, 1H), 7.00 (ddd, J=16.2, 9.8, 2.4 Hz, 1H), 6.46 (d, J=16.2 Hz,1H), 4.30 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Step B: Dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate

To a solution of 15 mL (64 mmol, 25% in methanol) of sodium methoxide in200 mL of methanol was added 5.5 mL (62 mmol) of methyl cyanoacetate andthe mixture was stirred at ambient temperature for 30 min. To thissolution was added 14 g (62 mmol) of the product of step A in 50 mL ofmethanol and the resulting yellow mixture was heated to reflux for 6 h.The mixture was then quenched carefully at ambient temperature with 1Naqueous hydrochloric acid (100 mL) and concentrated to remove methanol.The resulting mixture was extracted with three 300-mL portions of ethylacetate, and the organic phases combined and washed sequentially with 1Nhydrochloric acid, saturated aqueous sodium bicarbonate solution, andsaturated aqueous brine (100 mL each). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield aviscous oil. The crude material was purified by flash chromatography ona Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanesgradient) to give the title compound as a mixture of stereoisomers. ¹HNMR (CDCl₃): δ 7.33-6.96 (m, 2H), 4.23-3.93 (series of m, 2H), 3.81-3.67(series of s, 6H), 3.05-2.84 (m, 2H).

Step C:Methyl-trans-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate

To 450 mL of methanol at 0° C. was carefully added 30 mL of acetylchloride and the resulting solution was allowed to stir at ambienttemperature for 30 min. The resulting solution was added to 27 g (86mmol) of dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate fromStep B and the reaction mixture was then shaken with 5.0 g of platinum(IV) oxide under 50 psi of hydrogen for 20 h. The mixture was filteredthrough a pad of Celite and the filter cake washed with methanol anddichloromethane. The combined filtrate and washings were concentratedand then taken up in 400 mL of 1:1 methanol/toluene with potassiumcarbonate (28 g, 200 mmol). The resulting mixture was heated to refluxfor 4 h, then cooled to 0° C. and carefully quenched with 1Nhydrochloric acid until the solution was acidic by pH paper. Theresulting mixture was then extracted with six 300-mL portions of 3:1chloroform/isopropyl alcohol and the organic phases combined and washedwith saturated aqueous brine (300 mL). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield acolorless solid. This crude material was dissolved in 500 mL of 1:1diethyl ether/methanol and cooled to 0° C. To this solution was added 75mL (150 mmol) of trimethylsilyldiazomethane solution (2M in hexanes) inportions until a yellow color persisted. After warming to ambienttemperature, the solution was stirred an additional 2 h, thenconcentrated in vacuo. The title compound was collected as a colorlesscrystalline solid which was used without further purification. LC/MS288.3 (M+1).

Step D:Methyl-trans-1-[bis(4-methoxyphenyl)methyl]-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate

To a stirred solution of 6.6 g (23 mmol) of the product of Step C in 100mL of acetic acid was added 6.11 g (25 mmol) of 4,4′-dimethoxybenzhydrolfollowed by 5 mL of concentrated sulfuric acid and the resultingsolution was stirred at ambient temperature for 18 h. The solution wasthen concentrated and cooled 0° C. before quenching with ice water (100mL). The resulting mixture was extracted with three 300-mL portions ofethyl acetate, and the organic phases combined and washed sequentiallywith water, saturated aqueous sodium bicarbonate solution, and saturatedaqueous brine (200 mL each). The organic phase was dried over magnesiumsulfate, filtered, and evaporated in vacuo to yield a viscous oil. Thecrude material was purified by flash chromatography on a BiotageHorizon® system (silica gel, 0 to 50% ethyl acetate/hexanes gradient) togivemethyl-trans-1-[bis(4-methoxyphenyl)methyl]-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylateas a colorless solid. LC/MS 536.2 (M+23).

Step E:trans-1-[bis(4-methoxyphenyl)methyl]-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylicAcid

To a solution of 5.9 g (11.5 mmol) of the product from Step D in 100 mLof 3:1 tetrahydrofuran/methanol was added 30 mL (30 mmol) of a 1Naqueous lithium hydroxide solution and the resulting mixture was stirredat 60° C. for 2 h. The solution was concentrated and acidified with 100mL of 1N aqueous hydrochloric acid. The resulting mixture was thenextracted with three 250-mL portions of ethyl acetate, and the organicphases combined and washed sequentially with 1N hydrochloric acid andsaturated aqueous brine (100 mL each). The organic phase was dried overmagnesium sulfate, filtered, and evaporated in vacuo to yield the titleacid as a colorless foamy solid that was used without furtherpurification. LC/MS 522.2 (M+23).

Step F:Benzyl[trans-1-[bis(4-methoxyphenyl)methyl]-6-oxo-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 5.4 g (9.7 mmol) of the product of Step E in 60 mL of toluene wasadded 1.8 mL (12 mmol) of triethylamine followed by 2.8 mL (13 mmol) ofdiphenylphosphoryl azide. After stirring at ambient temperature for 30min, the reaction mixture was warmed to 70° C. for 30 min, then slowlyheated to reflux for an additional 2 h. The reaction mixture was cooledto ambient temperature, 3.2 g (30 mmol) of benzyl alcohol was added, andthe reaction mixture was heated to reflux for 5 h. The solution was thencooled to ambient temperature and quenched with 1N aqueous hydrochloricacid (100 mL) The resulting mixture was extracted with three 150-mLportions of ethyl acetate, the organic phases combined and washedsequentially with 1N hydrochloric acid, saturated aqueous sodiumbicarbonate solution, and saturated aqueous brine (100 mL each). Theorganic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a viscous crude oil. The crude material waspurified by flash chromatography on a Biotage Horizon® system (silicagel, 0 to 40% ethyl acetate/hexanes gradient) to give the title compoundas a colorless crystalline solid. LC/MS 605.6 (M+1).

Step G:tert-Butyl[(3R,4R)-6-oxo-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 8.5 g (14 mmol) of the product from Step F in 150 mL of methanol wasadded 4.4 g (20 mmol) of di-tert-butyldicarbonate and the solution wasshaken with 1.0 g of palladium hydroxide (20% on carbon) under 1 atm ofhydrogen for 12 h. The mixture was filtered through a pad of Celite andthe filter cake washed with methanol and dichloromethane. The combinedfiltrate and washings were concentrated and purified by flashchromatography on a Biotage Horizon® system (silica gel, 0 to 40% ethylacetate/hexanes gradient) to give the title compound as a colorlesscrystalline solid. Chiral HPLC separation (ChiralCel OD column, 20%methanol/carbon dioxide) gave the 3S,4S enantiomer A as the more mobileeluting compound and the 3R,4R enantiomer B, as the less mobile elutingcompound.

To 5.8 g (10 mmol) of the above 3R,4R enantiomer in 150 mL of 5:1acetonitrile/water solution at 0° C. was added 15 g (28 mmol) of cerium(IV) ammonium nitrate (CAN) and the reaction mixture was stirred at 0°C. for 60 min. The reaction mixture was then quenched at ambienttemperature with saturated NaHSO₃ solution (30 mL) and 1N hydrochloricacid (100 mL). The resulting mixture was then extracted with four 200-mLportions of 3:1 chloroform/isopropyl alcohol and the organic phasescombined and washed with 1N hydrochloric acid (200 mL) and saturatedaqueous brine (200 mL). The organic phase was then dried over magnesiumsulfate, filtered, and evaporated in vacuo to yield a colorless solid.This crude material was then purified by flash chromatography on aBiotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanesgradient) to give the title compound as a pale yellow solid. LC/MS 345.2(M+1).

tert-Butyl[(3R,4R)-6-oxo-4-(2,5-difluorophenyl)piperidin-3-yl]carbamate

The title compound was prepared as described above for Intermediate 1,starting with 2,5-difluorobenzaldehyde. LC/MS 327.2 (M+1).

EXAMPLE 1

(7R,8R)-2-Methyl-7-(2,4,5-trifluorophenyl)-6,7,8,9-tetrhydropyride[3′,2′;4,5]imidazo[1,2-a]pyridine-8-amine tris trifluoroacetic acid salt StepA:tert-Butyl[(7R,8R)-4-chloro-2-methyl-7-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]imidazo[1,2-a]pyridin-8-yl]carbamate

To an oven-dried flask charged with 50 mg (0.15 mmol) of Intermediate 1,39 mg (0.22 mmol) of 2,4-dichloro-6-methylpyridin-3-amine, 2.5 mg (0.013mmol) of copper(I) iodide, 35 mg (0.25 mmol) of potassium carbonate, and1.5 mL of dry toluene was added 0.003 mL (0.05 mmol) ofN,N′-dimethylethylenediamine and the mixture was heated to reflux for 24h. The mixture was cooled to ambient temperature and diluted with 10 mLof ethyl acetate. The ethyl acetate solution was washed with 5 mL of a1:1 mixture of saturated sodium bicarbonate solution and saturatedaqueous brine. The layers were separated, and the organic phase wasdried over anhydrous magnesium sulfate, filtered and evaporated invacuo. The crude oil was purified by preparative thin layerchromatography using an Analtech® 1000 micron plate (50% hexane/ethylacetate) to give the title compound as a viscous oil. LC/MS 467.1 (M+1),469.0 (M+2).

Step B:tert-Butyl[(7R,8R)-2-methyl-7-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]imidazo[1,2-a]pyridin-8-yl]carbamate

To 19 mg (0.04 mmol) of the product from Step A in 4 mL of methanol wasadded 10 mg of 20% palladium hydroxide on carbon. The reaction mixturewas purged with hydrogen gas and held under 1 atmosphere of hydrogen for1 h. The mixture was filtered through a pad of Celite and the filtercake was successively washed with three 4-mL portions of methanol. Thecombined filtrate and washings were concentrated and used withoutfurther purification. LC/MS 433.1 (M+1).

Step C:(7R,8R-2-Methyl-7-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]imidazol[2-a]pyridine-8-aminetris trifluoroacetic acid salt

To the product from Step B was added 4 mL of 1:1dichloromethane/trifluoroacetic acid and the solution was stirred for 60min then concentrated in vacuo. The residue was purified by reversephase HPLC (YMC Pro-C18 column, gradient elution, 0% to 65%acetonitrile/water with 0.1% TFA) to afford the title compound as awhite foam. LC/MS 333.1 (M+1).

EXAMPLE 2

(7R,8R)-8-(2,4,5-Trifluorophenyl)-6,7,8,9-tetrahydropyrido[2′,3′:4,5]imidazo[1,2-a]pyridine-7-amine

The title compound was prepared essentially following the procedure inExample 1, staring with 3-bromopyridine-2-amine. LC/MS 319.1 (M+1).

EXAMPLE 3

(7R,8R)-7-(2,5-Difluorophenyl)-6,7,8,9-tetrahydropyrido[1,2-e]purin-8-amine

The title compound was prepared essentially following the procedure inExample 1, staring with 4-iodopyrimidin-5-amine and using Intermediate2. LC/MS 302.2 (M+1).

EXAMPLE 4

(7R,8R)-8-(2,5-Difluorophenyl)-6,7,8,9-tetrahydropyrido[2,1-f]purin-7-amine

The title compound was prepared essentially following the procedure inExample 1, staring with 5-bromopyrimidin-4-amine and using Intermediate2. LC/MS 302.2 (M+1).

EXAMPLE 5

(7R,8R)-7-(2,4,5-Trifluorophenyl)-6,7,8,9-tetrahydropyrido[2′,1′:2,3]imidazo[4,5-c]pyridazin-8-amine

The title compound is prepared essentially following the procedure inExample 1, staring with 3,5-dichloropyridazin-4-amine.

EXAMPLE 6

(7R,8R)-7-(2,4,5-Trifluorophenyl)-6,7,8,9-tetrahydropyrido[1′,2′:1,2]imidazo[4,5-d]pyridazin-8-amine

The title compound is prepared essentially following the procedure inExample 1, staring with 5-chloropyridazin-4-amine and omitting Step B.

EXAMPLE 7

(7R,8R)-8-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[1′,2′:1,2]imidazo[4,5-c]pyridazin-7-amine

The title compound is prepared essentially following the procedure inExample 1, staring with 4-chloropyridazin-3-amine, and omitting Step B.

EXAMPLE 8

(7R,8R)-7-(2,4,5-Trifluorophenyl)-6,7,8,9-tetrahydropyrdo[1′,2′:1,2]imidazo[4,5-b]pyrazin-8-amine

The title compound is prepared essentially following the procedure inExample 1, staring with 3,5-dibromopyrazin-2-amine.

Example of a Pharmaceutical Formulation

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any of Examples 1-8, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein each n is independently 0, 1, 2 or 3; Ar is phenyl unsubstituted or substituted with one to five R² substituents; each R² is independently selected from the group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, unsubstituted or substituted with one to five halogens, and C₁₋₆ alkoxy, unsubstituted or substituted with one to five halogens; W, X, Y, and Z are selected from the following: wherein W is N; and X, Y, and Z are CR¹; wherein Z is N; and W, X, and Y are CR¹; wherein W and Y are N; and X and Z are CR¹; wherein X and Z are N; and W and Y are CR¹; wherein W and X are N; and Y and Z are CR¹; wherein X and Y are N; and W and Z are CR¹; wherein Y and Z are N; and W and X are CR¹; wherein W and Z are N; and X and Y are CR¹; each R¹ is independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, nitro, C₁₋₁₀ alkoxy, wherein alkoxy is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy, C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy, (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected hydroxy, halogen, cyano, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, cyano, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, cyano, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, cyano, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH₂)_(n)—COOH, (CH₂)_(n)—COOC₁₋₆ alkyl, (CH₂)_(n)—NR³R⁴, (CH₂)_(n)—CONR³R⁴, (CH₂)_(n)—OCONR³R⁴, (CH₂)_(n)—SO₂NR³R⁴, (CH₂)_(n)—SO₂R⁵, (CH₂)_(n)—SOR⁵, (CH₂)_(n)—SR⁶, (CH₂)_(n)—NR⁶SO₂R⁵, (CH₂)_(n)—NR⁶CONR³R⁴, (CH₂)_(n)—NR⁶COR⁶, and (CH₂)_(n)—NR⁶CO₂R⁵; wherein any individual methylene (CH₂) carbon atom in (CH₂)_(n) is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; R³ and R⁴ are each independently selected from the group consisting of hydrogen, (CH₂)_(n)-phenyl, (CH₂)_(n)—C₃₋₆ cycloalkyl, and C₁₋₆ alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen and hydroxy and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; or R³ and R⁴ together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; each R⁵ is independently C₁₋₆ alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen and hydroxy; and R⁶ is hydrogen or R⁵.
 2. The compound of claim 1 wherein each R² is independently selected from the group consisting of fluorine, chlorine, methyl, and trifluoromethyl.
 3. The compound of claim 1 of structural formula Ia or Ib having the indicated stereochemical configuration at the two stereogenic carbon atoms marked with an *:


4. The compound of claim 3 of structural formula Ia having the indicated absolute stereochemical configuration at the two stereogenic carbon atoms marked with an *:


5. The compound of claim 4 which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
 7. The pharmaceutical composition of claim 6 additionally comprising metformin.
 8. A method for treating non-insulin dependent (Type 2) diabetes in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of a compound of claim
 1. 